Treatment of sleep disorders using sleep target modulators

ABSTRACT

The invention is directed to compositions used for treating sleep disorders. In addition, the invention provides convenient methods of treatment of a sleep disorder. Furthermore, the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of ester derivatized trazodone compounds for the treatment of sleep disorders.

REFERENCE TO RELATED APPLICATION

This application claims priority to pending U.S. Provisional PatentApplication Attorney Docket Number HPZ-010-1 (Application No.60/349,912)filed on Jan. 18, 2002, and pending U.S. Provisional Patent ApplicationAttorney Docket Number HPZ-010-2 (Application No.60/357,320) filed onFeb. 15, 2002. This application is also related to pending U.S.Provisional Patent Application Serial No. 60/______ (Attorney DocketNumber HPZ-010-3), filed on even date herewith, entitled “Treatment ofSleep Disorders Using Sleep Target Modulators”. The entire content ofeach of the above-identified applications is hereby incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Difficulties in falling asleep, remaining asleep, sleeping for adequatelengths of time, or abnormal sleep behavior are common symptoms forthose suffering with a sleep disorder. A number of sleep disorders,e.g., insomnia or sleep apnea, are described in the online Merck Manualof Medicinal Information.

Current treatment of many sleep disorders include the use ofprescription hypnotics, e.g., benzodiazapines, that may behabit-forming, lose their effectiveness after extended use, andmetabolize more slowly for certain designated groups, e.g., elderlypersons, resulting in persisting medicative effects.

Other, more mild manners of treatment include over-the-counterantihistamines, e.g., diphenhydramine or dimenhydrinate, which are notdesigned to be strictly sedative in their activity. This method oftreatment is also associated with a number of adverse side effects,e.g., persistence of the sedating medication after the prescribed timeof treatment, or the so-called “hangover effect”. Many of these sideeffects result from nonspecific activity in both the periphery as wellas the Central Nervous System (CNS) during this period of extendedmedication.

SUMMARY OF THE INVENTION

A need exists for the development of new compositions used for theimproved treatment of sleep disorders that remain active for a discreteperiod of time to reduce side effects, such as the “hangover effect.”

Therefore, the invention is directed to compositions used for treatingsleep disorders. In addition, the invention provides convenient methodsof treatment of a sleep disorder. Furthermore, the invention providesmethods of treating sleep disorders using compositions that remainactive for a discrete period of time to reduce side effects.

More specifically, the invention is directed to the compositions and useof ester derivatized trazodone compounds for the treatment of sleepdisorders.

Thus, in one aspect of the invention, the invention is directed to amethod of treating a serotonin receptor associated disorder. The methodcomprises administering an effective amount of a therapeutic compound toa subject, such that the disorder is treated. Accordingly, thetherapeutic compound can have the formula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q, and r areindependently 0 or 1, and r and q are 0 when MR is the ester group.

Another aspect of the invention is a method of treating a serotoninreceptor associated disorder, comprising administering to a subject aneffective amount of a therapeutic compound, such that the disorder istreated. Accordingly, the therapeutic compound can have the formula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

In another aspect of the invention, the invention is a method oftreating a sleep disorder. The method comprises administering aneffective amount of a therapeutic compound, such that the sleep disorderis treated, wherein the compound has a favorable biological property(FBP).

An additional aspect of the invention is a method of treating a sleepdisorder. The method comprises administering an effective amount of atherapeutic compound to a subject, such that the sleep disorder istreated. Accordingly, the therapeutic compound is trazodone compoundthat contains a moiety selected and positioned, such that a wakepromoting metabolite is not formed. The therapeutic compound can havethe formula:[EG]_(r)-(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the half-life of the therapeutic compound, SP₁ andSP₂ are spacer molecules, n, q, and r are independently 0 or 1, and rand q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound.

Another aspect of the invention is directed to a method of treating asleep disorder. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disorder istreated. Accordingly, the therapeutic compound can have the formula:[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is a method of modulating a serotoninreceptor associated disorder target. The method comprises administeringan effective amount of a therapeutic compound to a subject, such thatthe disorder target is modulated, wherein the therapeutic compoundcomprises the formula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q; and r areindependently 0 or 1, and r and q are 0 when MR is the ester group.

Another aspect of the invention is a method of modulating a serotoninreceptor associated disorder target. The method comprises administeringan effective amount of a therapeutic compound to a subject, such thatthe disorder target is modulated, wherein the therapeutic compoundcomprises the formula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of modulating a sleepdisorder target.

The method comprises administering an effective amount of a therapeuticcompound to a subject, such that the sleep disorder target is modulated,wherein the therapeutic compound comprises the formula:[EG]_(r)-(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the s half-life of the therapeutic compound, SP₁ andSP₂ are spacer molecules, n, q, and r are independently 0 or 1, and rand q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound.

An additional aspect of the invention is a method of modulating a sleepdisorder target. The method comprises administering an effective amountof a therapeutic compound to a subject, such that the sleep disordertarget is modulated, wherein the therapeutic compound comprises theformula:[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is a compound comprising the formula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q, and r areindependently 0 or 1, and r and q are 0 when MR is the ester group.

In an additional aspect, the invention is a compound comprising theformula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

One aspect of the invention is a compound comprising the formula:[EG]_(r)-(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the half-life of the therapeutic compound, SP₁ andSP₂ are spacer molecules, n, q, and r are independently 0 or 1, and rand q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound.

A further aspect of the invention is a compound comprising the formula:[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutic compound as prepared according to themethodology of this invention, and a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to compositions used for treating sleepdisorders. In addition, the invention provides convenient methods oftreatment of a sleep disorder. Furthermore, the invention providesmethods of treating sleep disorders using compositions that remainactive for a discrete period of time to reduce side effects. Morespecifically, the invention is directed to the compositions and use ofester derivatized trazodone compounds for the treatment of sleepdisorders.

METHODS OF THE INVENTION

One embodiment of the invention is a method of treating a serotoninreceptor associated disorder. The method comprises administering aneffective amount of a therapeutic compound to a subject, such that thedisorder is treated. Accordingly, the therapeutic compound can have theformula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q, and r areindependently 0 or 1, and r and q are 0 when MR is the ester group. Incertain embodiments, the disorder is a sleep disorder.

The language “serotonin receptor antagonist” or “SR” is intended toinclude antagonists for the receptors for serotonin or 5-HT(5-hydroxytryptamine), i.e., compounds that inhibit the activity of theserotonin receptor and agents that down-regulate (i.e., inhibit) thesynthesis or production of the serotonin receptor.

The language “serotonin receptor” is intended to include receptors forserotonin or 5-HT (5-hydroxytryptamine). In certain embodiments of theinvention, the receptor is the 5-HT₂ receptor, which belongs to thefamily of rhodopsin-like signal transducers, distinguished by theirseven-transmembrane configuration and their functional linkage toG-proteins. While all the receptors of the serotonin type are recognizedby serotonin, they are pharmacologically distinct and are encoded byseparate genes. These receptors, known as subtypes, are generallycoupled to different second messenger pathways that are linked throughguanine-nucleotide regulatory (G) proteins. In certain embodiments,5-HT₂ receptors activate phospholipase C pathways, stimulating breakdownof polyphosphoinositides.

The 5-HT₂ subfamily—is divided into three receptor subtypes: 5-HT_(2A),5-HT_(2B), and 5-HT_(2C). The human 5-HT_(2C) receptor was firstisolated and cloned in 1987, and the human 5-HT_(2A) receptor was firstisolated and cloned in 1990. These two receptors are thought to be thesite of action of hallucinogenic drugs. Additionally, antagonists to the5-HT_(2A) and 5-HT_(2C) receptors are believed to be useful in treatingdepression, anxiety, psychosis and eating disorders.

In specific embodiments of the invention, the serotonin receptor is a5-HT_(2A) receptor. In certain embodiments, the 5-HT_(2A) receptor is aspecific receptor, which has low affinity for other 5-HT receptorsubtypes. Alternatively, the 5-HT_(2A) receptor is a general 5-HT_(2A)receptor, which has a significant affinity to two or more 5-HT receptorsubtypes.

The language “a serotonin receptor associated disorder” is intended toinclude any disorder that is associated with the 5-HT receptor. Incertain embodiments of the invention, the disorder is associated withthe 5-HT₂ receptor, e.g., the 5-HT_(2A) receptor. Serotonin is thoughtto play a role in processes related to learning and memory, sleep,thermoregulation, mood, motor activity, pain, sexual and aggressivebehaviors, appetite, neurodegenerative regulation, and biologicalrhythms. Moreover, serotonin has been linked to pathophysiologicalconditions such as anxiety, depression, obsessive-compulsive disorders,schizophrenia, suicide, autism, migraine, emesis, alcoholism andneurodegenerative disorders.

Exemplary 5-HT₂ antagonists which are considered to be within the scopeof the present invention include, but are not limited to adinazolam,allobarbital, alonimid, alprazolam, amitriptyline, amobarbital,amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione,butabarbital, butalbital, capuride, carbocloral, chloral betaine,chloral hydrate, chlordiazepoxide, clomipramine, cloperidone,clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol,diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin,estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, triazolam, trepipam, tricetamide, triclofos,trifluoperazine, trimetozine, trimipramine, uldazepam, valproate,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof.

Another embodiment of the invention is a method of treating a serotoninreceptor associated disorder, comprising administering to a subject aneffective amount of a therapeutic compound, such that the disorder istreated. Accordingly, the therapeutic compound can have the formula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a compound comprising the formula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q, and r areindependently 0 or 1, and r and q are 0 when MR is the ester group.

In an additional aspect, the invention is a compound comprising theformula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another aspect of the invention is a method of modulating a serotoninreceptor associated disorder target. The method comprises administeringan effective amount of a therapeutic compound to a subject, such thatthe disorder target is modulated, wherein the therapeutic compoundcomprises the formula:[EG]_(r)-(SP₂)_(q)-[SR]-(SP₁)_(n)-[MR]wherein SR is a serotonin receptor antagonist, MR is a metabolitereducing moiety that reduces the formation of wake promotingmetabolites, EG is an ester group that modifies the half-life of thetherapeutic compound, SP₁ and SP₂ are spacer molecules, n, q, and r areindependently 0 or 1, and r and q are 0 when MR is the ester group.

Another aspect of the invention is a method of modulating a serotoninreceptor associated disorder target. The method comprises administeringan effective amount of a therapeutic compound to a subject, such thatthe disorder target is modulated, wherein is the therapeutic compoundcomprises the formula:[SR]-(SP)_(n)-[EG]wherein SR is a serotonin receptor antagonist, EG is an ester group thatmodifies the half-life of the therapeutic compound, SP is a spacermolecule, and n is 0 or 1.

Another embodiment of the invention is a method of treating a sleepdisorder. The method of treating comprises administering to a subject aneffective amount of a therapeutic compound, such that the sleep disorderis treated.

The language “sleep disorder,” is art recognized and includes disordersor states that affect a subjects ability to sleep, and which aretreatable by the compounds described herein. Sleep disorders generallyinvolve disturbances of sleep that affect a subject's ability to falland/or stay asleep, and involve sleeping too little, too much orresulting in abnormal behavior associated with sleep. Examples include,but are not limited to disturbed biological and circadian rhythms; andsleep disturbances associated with such diseases as neurologicaldisorders, neuropathic pain and restless leg syndrome; allergies;tolerance to narcotics or withdrawal from narcotics; sleep apnea;narcolepsy, insomnia; Disorders of Initiating and Maintaining Sleep(insomnias) (“DIMS”) which can arise from psychophysiological causes, asa consequence of psychiatric disorders particularly related to anxiety),from drugs and alcohol use and abuse (particularly during withdrawalstages), childhood onset DIMS, nocturnal myoclonus and restless legs andnon specific REM disturbances as seen in aging; parasomnia; jet-lagsyndrome; hypersomnia, sleep apnea, REM sleep interruptions, shiftworkers' sleep disturbances, dysomnias, night terror, insomniasassociated with depression or with emotional/mood disorders, as well assleep walking and enuresis, as well as sleep disorders which accompanyaging, mental and physical disorders associated with travel across timezones and with rotating shift-work schedules, or syndromes such asfibromyalgia that are manifested by non-restorative sleep and musclepain or sleep apnea which is associated with respiratory disturbancesduring sleep; and drug abuse. Difficulties in falling asleep, remainingasleep, sleeping for adequate lengths of time, or abnormal sleepbehavior are common symptoms for those suffering with a sleep disorder.A number of sleep disorders, e.g., insomnia or sleep apnea, aredescribed in the online Merck Manual of Medicinal Information.

The administration to a subject of an appropriate amount of a compoundof the invention, is useful, for example, in the prevention or treatmentof the following conditions to achieve chronobiological effects and/orto alleviate circadian rhythm phase disturbances: disorders of thesleep-wake schedule; jet lag; shift work; people who have a maladaptionto work and off-work schedules; medical residents, nurses, firemen,policemen or those whose duties require alertness and wakefulness atevening or nighttime hours, or those deprived of sleep for variousperiods because of their duties or responsibilities; animal workers;athletes who wish to reset their internal clock to a more beneficialtime; the infantry, or other members of the armed forces whose dutiesrequire extreme levels of alertness and wakefulness, and those who maybe sleep deprived in the performance of these duties; submariners, orpeople confined for research, exploration or industrial purposes belowthe seas; miners, spelunkers, researchers or those confined beneath theEarth; astronauts in orbit around the Earth, on missions in space to theEarth's moon or to the planets or out of the solar system, or intraining for such missions; the blind or sight-impaired or those personswhose ability to distinguish differences in light and dark may bepermanently or temporarily impaired; psychiatric patients; insomniacs;the comatose, or those who need to be maintained in a state ofunconsciousness for medical, psychiatric or other reasons; residents ofthe far North or Antarctica, or those persons who live in a climate orclimates which possess abnormal amounts of light or darkness; thosesuffering from seasonal affective disorder (SAD), winter depression, orother forms of depression; the aged; Alzheimer's disease patients, orthose suffering from other forms of dementia; patients who requiredosages of medication at appropriate times in the circadian cycles;patients suffering from delayed sleep phase syndrome, advanced sleepphase syndrome, or non-24 hr sleep phase syndrome; and patientssuffering from primary or secondary insomnia or circadian rhythm-relatedinsomnia. The present invention is useful, for example, in theprevention or treatment of conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules.

The language “insomnia” is characterized by difficulty in sleeping ordisturbed sleep patterns. Insomnia may be of a primary nature withlittle apparent relationship to immediate somatic or psychic events, orsecondary to some acquired pain, anxiety or depression, and is furtherdescribed by Mondadori et al. in U.S. Pat. No. 6,277,864.

The terms “treating” or “treatment” include administering atherapeutically effective compound sufficient to reduce or eliminate atleast one symptom of the state, disease or disorder, e.g., a sleepdisorder. It will be appreciated to those skilled in the art thatreference herein to treatment extends to prophylaxis (prevention) aswell as the treatment of the noted diseases/disorders and symptoms.

The language “administering” includes delivery to a subject by any meansthat does not affect the ability of the therapeutic compound to performis intended function. The therapeutic compound may be administered byany means that sufficiently treats the disorder target. Administrationincludes, but is not limited to parenteral, enteral, and topicaladministration. While it is possible for a compound of the presentinvention to be administered alone, it is preferable to administer thecompound as a pharmaceutical composition, which includes compositionsthat comprise the compounds of the present invention and apharmaceutically acceptable carrier. In a specific embodiment, thetherapeutic compound is administered orally.

Administration also includes the use of an additional modulating factor(AMF) in “combination therapy.” The language “additional modulatingfactor (AMF)” includes additional factors, such as additionaltherapeutics or abnormalities in the subject, e.g., a chemicalimbalance. It should be understood that the additional modulating factormay be directed to or affect the same or a different disorder target asthat being modulated by the compounds of the present invention. Thelanguage “combination therapy” includes the co-administration of themodulating compound of the present invention in the presence of anadditional modulating factor, e.g., an additional therapeutic agent.Administration of the modulating compound may be first, followed by theother therapeutic agent; or administration of the other therapeuticagent may be first, followed by the modulating, e.g., inhibiting,compound. The other therapeutic agent may be any agent which is known inthe art to treat, prevent, or reduce the symptoms of the targeteddisorder, e.g., a sleep disorder. Furthermore, the other therapeuticagent may be any agent of benefit to the patient when administered incombination with the administration of a modulating, e.g., inhibiting,compound.

For example, a therapeutic compound of the invention may be administeredin conjunction with a variety of commercially-available drugs,including, but not limited to, antimicrobial agents, such aspentamidine, lomefloxacin, metronidazole; fungistatic agents; germicidalagents; hormones; antipyretic agents; antidiabetic agents;bronchodilators, such as aminophylline; antidiarrheal agents, such asdiphenoxylate hydrochloride with atropine sulfate; antiarrhythmicagents, such as disopyramide phosphate and bidisomide; coronary dilationagents; glycosides; spasmolytics; antihypertensive agents, such asverapamil and verapamil hydrochloride and their enantiomers, andbetaxolol; antidepressants; antianxiety agents; other psychotherapeuticagents, such as zolpidem, cycloserine and milacemide; corticosteroids;analgesics, such as misoprostol with diclofenac; contraceptives, such asethynodiol diacetate with ethinyl estradiol, and norethynodrel withmestranol; nonsteroidal anti-inflammatory drugs, such as oxaprozen;blood glucose lowering agents; cholesterol lowering agents;anticonvulsant agents; other antiepileptic agents; immunomodulators;antioholinergics; sympatholytics; sympathomimetics; vasodilatory agents;anticoagulants; antiarrhythmics, such as disopyramide or disobutamide;prostaglandins having various pharmacologic activities, such asmisoprostol and enisoprost; diuretics, such as spironolactone andspironolactone with hydrochlorothiazide; sleep aids, such as zolpidemtartrate; antihistaminic agents; antineoplastic agents; oncolyticagents; antiandrogens; antimalarial agents,; antileprosy agents; andvarious other types of drugs. See Goodman and Gilman's The Basis ofTherapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and TheMerck Index (Eleventh Edition, Merck & Co., Inc., USA, 1989), each ofwhich is incorporated herein by reference.)

The other therapeutic agent may also be a modulating compound. Inaddition, the compounds of the present invention can also beadministered in combination with other known therapies for the targetdisorder. For example, the trazodone compound may be administered inconjunction with other compounds that are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including compounds known in the art to beuseful for suppressing or stimulating melatonin production, such as,melatonergic agents, noradrenergic and serotonergic re-uptake blockers,alpha-1-noradrenergic agonists, monamine oxidase inhibitors,neuropeptide Y agonists or antagonists; neurokinin-1 agonists; substanceP; beta-adrenergic blockers and benzodiazepines, such as atenolol; othercompounds that are known in the art to be useful for stimulatingmelatonin production including tricyclic antidepressants andalpha-2-adrenergic antagonists; melatonin precursors such as tryptophan,5-hydroxytryptophan, serotonin and N-acetylserotonin; as well asmelatonin analogs, melatonin agonists and melatonin antagonists, andmelatonin, itself. In addition, the trazodone compound may beadministered in conjunction with other compounds which are known in theart to be useful for enhancing sleep quality and preventing and treatingsleep disorders and sleep disturbances, including e.g., sedatives,hypnotics, anxiolytics, antipsychotics, antianxiety agents, minortranquilizers, benzodiazepines, barbituates, and the like, as well asadmixtures and combinations thereof. The trazodone compound may also beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In addition, the trazodone compound may be administered in associationwith therapeutically effective amounts of one or more adjunct activeingredients selected from decongestants, aspirin, (acetylsalicylicacid), acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs),cough suppressants, and expectorants. Said adjunct ingredients are dosedat levels known to those skilled in the art and as described in thePhysicians' Desk Reference. Representative NSAIDs include, but are notlimited to, naproxen, ibuprofen, ketoprofen, benoxaprofen,fluribiprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, albinoprofen,tiaprofenic acid, fluprofen, bucloxic acid, or pharmaceuticallyacceptable salts thereof.

Furthermore, a compound of the invention also may be administered inconjunction with any one or combination of the commercially-available,over-the-counter or prescription medications, including, but not limitedto Avobenzene/padimate-O, ACCUPRIL® tablets (quinapril hydrochloride),Accutane capsules (isotretinoin), Achromycin V capsules (themonohydrochloride of (4S-(4α,4a.alpha.,5aα,6β,12aα,))-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,6,10,12,12a-pentBPydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide),Actifed cough syrup (codeine phosphate, triprolidine hydrochloride andpseudoephedrine hydrochloride), Aldactazide tablets (spironolactone andhydrochlorothiazide), ALDOCLOR® tablets (methyldopa and chlorothiazide),Aldoril tablets (methyldopa-hydrochlorothiazide), Alferon® N injection(interferon .alpha-n3 (human leukocyte derived)), ALTACE™ capsules(ramipril), AMBIEN® tablets (zolpidem tartrate), Anafranil capsules(clomipramine hydrochloride), ANAPROX® tablets (naproxen sodium),Ancobon capsules (flucytosine), Ansaid tablets (flurbiprofen),Apresazide capsules (hydralazine hydrochloride and hydrochlorothiazide),Asendin tablets (2-chloro-11-(1-piperazinyl)dibenz(b,f)(1,4)-oxazepine),Atretol™ tablets (carbamazepine), Aureomycin ophthalmic ointment(chlortetracycline hydrochloride), Azo Gantanol® tablets(sulfamethoxazole and phenazopyridine hydrochloride), Azo Gantrisintablets (sulfisoxazole and phenazopyridine hydrochloride), Azulfidine®tablets and EN-tabs (5-((p-(2-pyridylsulfamoyl)phenyl)-azo)salicylicacid), Bactrim tablets (trimethoprim and sulfamethoxazole), Bactrim I.V.infusion (trimethoprim and sulfamethoxazole), Bactrim pediatricsuspension (trimethoprim and sulfamethoxazole), Bactrim suspension(trimethoprim and sulfamethoxazole), Bactrim tablets (trimethoprim andsulfamethoxazole), Benadryl® capsules (diphenhydramine hydrochlorideUSP), Benadryl® kapseals (diphenhydramine hydrochloride USP), Benadryl®tablets (diphenhydramine hydrochloride USP), Benadryl® parenteral(diphenhydramine hydrochloride USP), Benadryl® steri-vials, ampoules,and steri-dose syringe (diphenhydramine hydrochloride USP), Capotentablets (captopril), Capozide tablets (captopril-hydrochlorothiazide),Cardizem® CD capsules (diltiazem hydrochloride), Cardizem® SR capsules(diltiazem hydrochloride), Cardizem® tablets (diltiazem hydrochloride),Chibroxin sterile ophthalmic solution (with oral form) (norfloxacin),Children's Advil® suspension (ibuprofen), Cipro® I.V. (ciprofloxacin),Cipro® tablets (ciprofloxacin), Claritin tablets (loratadine), Clinoriltablets (sulindac), Combipres® tablets (clonidine hydrochloride andchlorthalidone), Compazine® injection (prochlorperazine maleate),Compazine® multi-dose vials (prochlorperazine maleate), Compazine®syringes (prochlorperazine maleate), Compazine® spansule capsules(prochlorperazine maleate), Compazine® suppositories (prochlorperazinemaleate), Compazine® syrup (prochlorperazine maleate), Compazine®tablets (prochlorperazine maleate), Cordarone tablets (amiodaronehydrochloride), Corzide tablets (nadolol and bendroflumethiazide),Dantrium capsules (dantrolene sodium), Dapsone tablets(4-4′diaminodiphenylsulfone), DAYPRO® caplets (oxaproxin), Declomycintablets (demeclacycline or (4S-(4α,4aα,5aα,6β,12aα))-7-Chloro-4-dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,6,10,12,12a-pentBPydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrochloride), DECONAMINE® capsules (chlorpheniramine maleate andd-psuedoephedrine hydrochloride), DECONAMINE® syrup (chlorpheniraminemaleate and d-psudoephedrine hydrochloride), DECONAMINE® tablets(chlorpheniramine maleate and d-psudoephedrine hydrochloride), Depakenecapsules (valproic acid), Depakene syrup (valproic acid), Depakotesprinkle capsules (divalproex sodium), Depakote tablets (divalproexsodium), DiaBeta® tablets (glyburide), Diabinese tablets(chlorpropamide), Diamox parenteral (acetazolamide), Diamox sequels(acetazolamide), Diamox tablets (acetazolamide), Dimetane-DC cough syrup(brompheniramine maleate, phenylpropanolamine hydrochloride and codeinephosphate), Dimetane-DX cough syrup (brompheniramine maleate,phenylpropanolamine hydrochloride and codeine phosphate), Dipentum®capsules (olsalazine sodium), Diucardin tablets (hydroflumethiazide),Diupres tablets (reserpine and chlorothiazide), Diuril oral suspension(chlorothiazide), Diuril sodium intravenous (chlorothiazide), Diuriltablets (chlorothiazide), Dolobid tablets (diflunisal), DORYX® capsules(doxycycline hyclate), Dyazide capsules (hydrochlorothiazide andtriamterene), Dyrenium capsules (triamterene), Efudex cream(5-fluorouracil), Efuidex solutions (5-fluorouracil), Elavil injection(amitriptyline HCl), Elavil tablets (amitriptyline HCl), Eldepryltablets (selegiline hydrochloride), Endep tablets (amitriptyline HCl),Enduron tablets (methyclothiazide), Enduronyl Forte tablets(methyclothiazide and deserpidine), Enduronyl tablets (methyclothiazideand deserpidine), Ergamisol tablets (levamisole hydrochloride), Esidrixtablets (hydrochlorothiazide USP), Esimil tablets (guanethidinemonosulfate USP and hydrochlorothiazide USP), Etrafon Forte tablets(perphenazine, USP and amitriptyline hydrochloride, USP), Etrafon 2-10tablets (perphenazine, USP and amitriptyline hydrochloride, USP),Etrafon tablets (perphenazine, USP and amitriptyline hydrochloride,USP), Etrafon-A tablets (perphenazine, USP and amitriptylinehydrochloride, USP), Eulexin capsules (flutamide), Exna tablets(benzthiazide), FUDR injection (floxuridine), Fansidar tablets(N1-(5,6-dinethoxy-4-pyrimidinyl) sulfanilamide (sulfadoxine) and2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (pyrimethamine),Feldene capsules (piroxicam), Flexeril tablets (cyclobenzaprinehydrochloride), FLOXIN® I.V. (ofloxacin injection), FLOXINS® tablets(ofloxacin), Fluorouracil injection (5-fluoro-2,4(1H,3H)-pyrimidinedione), Fulvicin tablets (griseofulvin), Gantanol®suspension (sulfamethoxazole), Gantanol® tablets (sulfamethoxazole),Gantrisin ophthalmic ointaent/solution (sulfisoxazole), Gantrisinpediatric suspension (sulfisoxazole), Gantrisin syrup (sulfisoxazole),Gantrisin tablets (sulfisoxazole), Glucotrol tablets (glipizide),Glynase PresTab tablets (glyburide), Grifuilvin V tablets(griseofulvin), Grifulvin oral suspension (griseofulvin), Gristactincapsules (griseofulvin), Grisactin tablets (griseofulvin), Gris-PEGtablets (griseofulvin), Grivate tablets (griseofulvin), Grivatesuspension (griseofulvin), Haldol Decanoate 50 injection aloperidoldecanoate), Haldol Decanoate 100 injection (haloperidol decanoate),Haldol tablets (haloperidol decanoate), Hibistat germicidal hand rinse(chlorhexidine gluconate), HISMANAL® tablets (astemizole), HydroDIURILtablets (hydrochlorothiazide), Hydromox tablets (quinethazone),Hydropres tablets (reserpine and hydrochlorothiazide), Inderide® tablets(propranolol hydrochloride and hydrochlorothiazide), Inderides capsule®(propranolol hydrochloride and hydrochlorothiazide), Intal inhaler(cromolyn sodium), Intron A injection (recombinant interferon.alpha.-2b), Lamprene capsules (clofazimine), Lasix oral solution(furosemide), Lasix tablets (furosemide), Lasix injection (furosemide),Limbitrol tablets (chlordiazepoxide and amitriptyline hydrochloride),Lodine capsules (etodolac), Lopressor HCT tablets (metoprolol tartrateUSP and hydrochlorothiazide USP), Lotensin tablets (benazeprilhydrochloride), LOZOL® tablets (indapamide), Ludiomil tablets(maprotiline hydrochloride USP), Marplan tablets (isocarboxazid),MAXAQUIN® tablets (lomefloxacin HCl), Maxzide tablets (triamterene USPand hydrochlorothiazide USP), Mellaril® concentrate (thioridazine),Mellarilg tablets (thioridazine), Mellaril-S suspension (thioridazine),Mepergan injection (meperidine hydrochloride and promethazinehydrochloride), Methotrexate tablets (methotrexate), Mevacor tablets(lovastatin), Micronase tablets (glyburide), Minizide capsules (prazosinhydrochloride and polythiazide), Minocin intravenous((4S-(4α,4aα,5aα,12aα))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride), Minocin oral suspension((4S-(4α,4aα.,5aα,12aα))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamidemonohydrochloride), Minocin capsules((4S-(4.alpha.,4a.alpha,5a.alpha,12a.alpha.))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride), Moduretic tablets (amilorideHCl-hydrochlorothiazide), Monodox® capsules (doxycycline monohydrate),Monopril tablets (fosinopril sodium), Children's Motrin liquidsuspension (ibuprofen), Motrin tablets (ibuprofen), Mykrox tablets(metolazone), NAPROSYN® suspension (naproxen), NAPROSYN® tablets(naproxen), Navane capsules (thiothixene), Navane intramuscular(thiothixene), NegGram caplets (nalidixic acid), NegGram suspension(nalidixic acid), Neptazane tablets (methazolamide), Nipent injection(pentostatin), Normodyne tablets (labetalol HCl), NOROXIN tablets(norfloxacin), Norpramin tablets (desipramine hydrochloride USP), oretictablets (hydrochlorothiazide), Oreticyl Forte tablets(hydrochlorothiazide and deserpidine), Orinase tablets (tolbutamide),Ornade capsules (phenylpropanolamine hydrochloride and chlorpheniraminemaleate), Orudis capsules (ketoprofen), Oxsoralen lotion(methoxypsoralen), PBZ tablets (tripelennamine hydrochloride USP),PBZ-SR tablets (tripelennamine hydrochloride USP), pHisoHex topicalemulsion (hexachlorophene), P & S PLUS® topical tar gel (crude coaltar), Pamelor® capsules (nortriptyline HCl), Pamelor® solution(nortriptyline HCl), Paxil tablets (paroxetine hydrochloride), Pediazoleoral suspension (erythromycin ethylsuccinate, USP and sulfisoxazoleacetyl, USP), Penetrex™ tablets (enoxacin), Pentasa capsules(mesalamine), Periactin syrup (cyproheptadine HCl), Periactin tablets(cyproheptadine HCl), Phenergan tablets (promethazine hydrochloride),Phenergan injection (promethazine hydrochloride), Phenergansuppositories (promethazine hydrochloride), Phenergan syrup(promethazine hydrochloride), Polytrim® ophthalmic solution(trimethoprim sulfate and polymyxin B sulfate), Pravachol (pravastatinsodium), Prinivil® tablets (lisinopril, MSD), Prinzide tablets(lisinopril-hydrochlorothiazide), Prolixin elixir (fluphenazinehydrochloride), Prolixin enanthate (fluphenazine hydrochloride),Prolixin injection (fluphenazine hydrochloride), Prolixin oralconcentrate (fluphenazine hydrochloride), Prolixin tablets (fluphenazinehydrochloride), ProSom tablets (estazolam), Prozac® oral solution(fluoxetine hydrochloride), Prozac® oral Pulvules® (fluoxetinehydrochloride), Pyrazinamide tablets (pyrazinamide), QUINAGLUTE® tablets(quinidine gluconate), Quinidex tablets (quinidine sulfate), Relafentablets (nabumetone), Ru-Tuss II capsules (chlorpheniramine maleate andphenylpropanolamine hydrochloride), Seldane tablets (terfenadine),Septra tablets (trimethoprim and sulfamethoxazole), Septra suspension(trimethoprim and sulfamethoxazole), Septra I.V. infusion (trimethoprimand sulfamethoxazole), Septra tablets (trimethoprim andsulfamethoxazole), Ser-Ap-Es tablets (reserpine USP, hydralazinehydrochloride USP and hydrochlorothiazide USP), Sinequan capsules(doxepin HCl), Solganal injection (aurothioglucose, USP), Stelazineconcentrate (trifluoperazine hydrochloride), Stelazine injection(trifluoperazine hydrochloride), Stelazine tablets (trifluoperazinehydrochloride), Surmontil capsules (trimipramine maleate), SYMMETRELcapsules and syrup (amantadine hydrochloride), Taractan concentrate(chlorprothixene), Taractan injectable (chlorprothixene), Taractantablets (chlorprothixene), TAVIST® syrup (clemastine fumarate, USP),TAVIST® tablets (clemastine fumarate, USP), TAVIST®-1 12 hour reliefmedicine (clemastine fumarate, USP), TAVIST®-D 12 hour relief medicine(clemastine fumarate, USP), Tegretol Tablets (carbamazepine USP),Tegretol suspension (carbamazepine USP), Temaril tablets (trimeprazinetartrate), Temaril syrup (trimeprazine tartrate), Temaril capsules(trimeprazine tartrate), TENORETIC® tablets (atenolol andchlorthalidone), Terramycin intramuscular solution (oxytetracycline),Thiosulfil Forte tablets (sulfamethizole), Thorazine ampuls(chlorpromazine hydrochloride), Thorazine concentrate (chlorpromazinehydrochloride), Thorazine multi-dose vials (chlorpromazinehydrochloride), Thorazine capsules (chlorpromazine hydrochloride),Thorazine suppositories (chlorpromazine hydrochloride), Thorazine syrup(chlorpromazine hydrochloride), Thorazine tablets (chlorpromazinehydrochloride), Timolide tablets (timolol maleate-hydrochlorothiazide),Tofranil ampuls (imipramine hydrochloride USP), Tofranil tablets(imipramine hydrochloride USP), Tofranil capsules (imipraminehydrochloride USP), Tolinase tablets (tolazamide), Triaminic ExpectorantDH (phenylpropanolamine hydrochloride and guaifenesin), Triaminic oralinfant drops (phenylpropanolamine hydrochloride, pheniramine maleate andpyrilamine maleate), Triavil tablets (perphenazine-amitriptyline HCl),Trilafon concentrate (perphenazine USP), Trilafon injection(perphenazine USP), Trilafon tablets (perphenazine, USP), Trinalintablets (azatadine maleate, USP, and pseudoephedrine sulfate, USP),Vaseretic tablets (enalapril maleate-hydrochlorothiazide), Vasosulfopthalmic solution (sulfacetamide sodium-phenylephrine hydrochloride),Vasotec I.V. (enalapril maleate), Vasotec tablets (enalapril maleate),Velban® vials (vinblastine sulfate, USP), Vibramycin capsules(doxycycline monohydrate), Vibramycin intravenous (doxycyclinemonohydrate), Vibramycin oral suspension (doxycycline monohydrate),Vibra-Tabs tablets (oxytetracycline), Vivactil tablets (protriptylineHCl), Voltaren tablets (diclofenac sodium), X-SEB T® shampoo (crude coaltar), Zaroxolyn tablets (metolazone), ZESTORETIC® oral (lisinopril andhydrochlorothiazide), ZESTRIL® tablets (lisinopril), ZITHROMAX™ capsules(azithromycin), Zocor tablets (simvastatin), ZOLOFT® tablets (sertralinehydrochloride) and others.

The term “pharmaceutically acceptable carrier” include apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a compound(s) of thepresent invention within or to the subject such that it can perform itsintended function. Typically, such compounds are carried or transportedfrom one organ, or portion of the body, to another organ, or portion ofthe body. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;phosphate buffer solutions; and other non-toxic compatible substancesemployed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient that canbe combined with a carrier material to produce a single dosage form willgenerally be that amount of the compound that produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made in asuitable machine by molding a mixture of the powdered compound moistenedwith an inert liquid diluent

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacilying agents and may be of a composition that releases the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in microencapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art. For example, such inert diluents, include but are notlimited to, water or other solvents, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrrhydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising. For example, a formulation of the invention may be preparedfrom cocoa butter, polyethylene glycol, a suppository wax or asalicylate, which is solid at room temperature, but liquid at bodytemperature, and will, therefore, melt in the rectum or vaginal cavityand release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders, which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally; and are of course given by formssuitable for each administration route. For example, the preparationsare administered in tablets or capsule form, by injection, inhalation,eye lotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

The terms “parenteral administration” and “administered parenterally” asused herein means modes of administration other than enteral and topicaladministration, usually by injection, and includes, without limitation,intravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intraarticular, subcapsular, subaracinoid,intraspinal and intrastemal injection and infusion.

The terms “systemic administration,” “administered systematically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, for example,subcutaneous administration, such that it enters the patient's systemand thus, is possibly subject to metabolism and other like processes.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compound employed, theage, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medicalarts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

The regimen of administration can affect what constitutes an effectiveamount. The disorder target modulators, e.g., sleep disorder targetmodulators, can be administered to the subject either prior to or afterthe onset of a sleep disorder associated state. Further, several divideddosages, as well as staggered dosages, can be administered daily orsequentially, or the dose can be continuously infused, or can be a bolusinjection. Further, the dosages of the disorder target modulators, e.g.,sleep disorder target modulators, compound(s) can be proportionallyincreased or decreased as indicated by the exigencies of the therapeuticor prophylactic situation.

The language “subject” includes animals (e.g., mammals, e.g., cats,dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears,primates (e.g., chimpanzees, gorillas, and humans) which are capable ofsuffering from a sleep associated disorder.

The language “therapeutically effective amount” of the compound is thatamount necessary or sufficient to treat or prevent a state associatedwith a disorder, e.g., sleep disorder. The effective amount can varydepending on such factors as the size and weight of the subject, thetype of illness, or the particular compound. For example, the choice ofthe therapeutic compound can affect what constitutes an “effectiveamount”. One of ordinary skill in the art would be able to study theaforementioned factors and make the determination regarding theeffective amount of the therapeutic compound without undueexperimentation.

The language “penetrates into the CNS” includes the favorable biologicalproperty of a compound of the current invention to pass through, orpenetrate, the blood brain barrier (BBB) and enter into the CNS.

The language “therapeutic compound” includes compounds of the inventioncapable of performing their intended function, e.g., treating sleepdisorders and/or modulating sleep targets. The therapeutic compounds ofthe invention are described in detail herein.

Accordingly, the therapeutic compound can have the formula:[EG]_(r)(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the half-life of the therapeutic compound, SP₁ andSP₂ are spacer molecules, n, q, and r are independently 0 or 1, and rand q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound.

Moreover, an ester moiety can function as the moiety that inhibits theformation of a wake promoting metabolite, Lie., MR, or a separate groupcan be used for that purpose. If a separate group is used to inhibit theformation of the wake-promoting metabolite, then an ester moiety canoptionally be positioned elsewhere in the drug so as to control itshalf-life through esterase catalyzed inactivation. However, if an estergroup is used to inhibit the formation of a wake promoting metabolitethen the same ester group can be, but is not necessarily, used tocontrol the half life of the drug.

The language “trazodone compound”, or “TZ” is intended to includetrazodone or analogs thereof The trazodone analogs include, but are notlimited to, trazodones containing substituents that do not significantlyeffect the analog's ability to perform its intended function.

The language “metabolism reducing moiety”, or “MR” is a moiety thatprovides the ability to reduce the metabolism of the therapeuticcompound such that there is a reduction in the wake promotingmetabolites formed. Alternatively, MR can be a moiety that modifies theactivity of the metabolite. Examples include functional moieties, e.g.,esters or alkyl groups, selected and positioned within the therapeuticdrug to provide the ability for a reduction in the wake promotingmetabolites formed. In certain embodiments, the MR provides the abilityto modulate the activity of the drug, e.g., half-life. In certainembodiments of the invention, the metabolism reducing moiety is an estergroup, EG. Alternatively, in particular embodiments of the invention theMR is alkyl, e.g., cyclopropyl or gem-dimethyl, as depicted below inTable 2.

The language “wake promoting metabolite” is intended to include ametabolite of the therapeutic compound, produced in vivo that reducesthe therapeutic effect on the sleep disorder. In certain embodiments,the wake promoting metabolite is meta-chlorophenylpiperazine (m-CPP).

The language “ester group” or “EG” are used interchangeably and areintended to include an organic ester functionality that is selected andpositioned within the compound providing the ability to modulate theactivity or modify the properties of the corresponding therapeuticcompound, e.g., half-life or metabolite formation. In certainembodiments, the EG modifies the half-life of the therapeutic compoundand/or reduces the formation of wake promoting metabolites. The organicester group may be terminal, e.g., a substituent, or internal. Thecarboxylate of the ester may be oriented from left to right or fromright to left, e.g., a reverse ester. Examples of esters of the currentinvention include, but are not limited to hydrocarbons andperfluorocarbons. In a preferred embodiment, the hydrocarbon possesses 1to 20 carbons. In certain embodiments, the hydrocarbon can be linear,branched, cyclic, aromatic, or a combination of saturated or unsaturatedaliphatic and aromatic groups, which are optionally substituted with O,N, S, and/or halogens and may additionally include a center ofchirality. In particular embodiments, the ester can be an n-propyl, anisopropyl, a t-butyl, an isobutyl, a cyclopentyl, a cyclohexyl, acycloheptyl, and a benzyl group.

In particular embodiments, the activity of the drug, e.g., half-life, ofthe therapeutic drug is modulated by controlling the rate of hydrolysisof the ester group by selection and positioning of steric bulk near theester carbonyl of the ester group, or by the incorporation of electronwithdrawing or donating moieties into, or adjacent to, the ester. Incertain embodiments, the steric bulk is provided by the selection of abulky ester group. In alternative embodiments the steric bulk isprovided by substitution selected and positioned on the TZ moiety nearthe carbonyl of the ester group.

The language “bulky ester” is intended to include an ester that hassufficient steric properties such that the rate of hydrolysis of thetherapeutic compound is modulated, e.g., reduced, such that the activityof the therapeutic compound is modified, e.g., the length of activity isincreased (i.e., the half-life of the therapeutic compound isincreased). Examples of bulky ester groups are depicted in Table 1.TABLE 1 Bulky Ester Groups For H1 Antagonists

Type A:

Type B:

The language “hydrocarbon” includes substituted or unsubstituted alkyl,alkenyl, alkynyl, or aryl moieties. The term “alkyl” includes saturatedaliphatic groups, including straight-chain alkyl groups (e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.),branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.),cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. The term alkyl further includesalkyl groups, which can further include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkyl has 6 or fewer carbon atoms in its backbone (e.g., C₁-C₆ forstraight chain, C₃-C₆ for branched chain), and more preferably 4 orfewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms intheir ring structure, and more preferably have 5 or 6 carbons in thering structure. The term C₁-C₆ includes alkyl groups containing 1 to 6carbon atoms.

Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). The term “alkyl” also includes the side chains of natural andunnatural amino acids.

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, benzene, phenyl, pyrrole, furan, thiophene, thiazole,isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole,isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and thelike. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings which are not aromatic so as to form apolycycle (e.g., tetralin).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, but thatcontain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups which include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including aLkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto five carbon atoms in its backbone structure. “Lower alkenyl” and“lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.

The term “acyl” includes compounds and moieties that contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” includealkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more carbons of the hydrocarbonbackbone, e.g., oxygen, nitrogen or sulfur atoms.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties. Examples ofhalogen substituted alkoxy groups include, but are not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, etc.

The term “amine” or “amino” includes compounds where a nitrogen atom iscovalently bonded to at least one carbon or heteroatom. The term “alkylamino” includes groups and compounds wherein the nitrogen is bound to atleast one additional alkyl group. The term “dialkyl amino” includesgroups wherein the nitrogen atom is bound to at least two additionalalkyl groups. The term “arylamino” and “diarylamino” include groupswherein the nitrogen is bound to at least one or two aryl groups,respectively. The term “alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group that is bound to at least onealkyl group and at least one aryl group. The term “alkaminoalkyl” refersto an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom that isalso bound to an alkyl group.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl, or alkynyl groups bound to an amino group boundto a carboxy group. It includes arylaminocarboxy groups that includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and“arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl andaryl moieties, respectively, are bound to a nitrogen atom which is inturn bound to the carbon of a carbonyl group.

The term “carbonyl” or “carboxy” includes compounds and moieties thatcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties that contain a carbonyl include aldehydes, ketones,carboxylic acids, amides, esters, anhydrides, etc.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietiesthat contain a carbon connected with a double bond to a sulfur atom.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “thioether” includes compounds and moieties that contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomthat is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated,” e.g., perfluorinated, generally refers to amoiety, e.g., perfluorocarbons, wherein all hydrogens are replaced byhalogen atoms, e.g., fluorine.

The terms “polycyclyl” or “polycyclic radical” refer to two or morecyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

In certain embodiments, the ester group or the metabolite reducingmoiety (EG or MR) does not substantially effect the biological activityof the therapeutic compound. Alternatively, in certain other embodimentsthe ester group or the metabolite reducing moiety (EG or MR)significantly effects the biological activity of the therapeuticcompound. In one embodiment, the ester group or the metabolite reducingmoiety (EG or MR) decreases the biological activity of the therapeuticcompound. Alternatively, in an another embodiment of the invention, theester group or the metabolite reducing moiety (EG or MR) improves thebiological activity of the therapeutic compound.

When the ester is a methyl or an ethyl ester, the formulation of thetherapeutic compound is formulated to sufficiently treat the targetdisorder. In addition, formulations of the therapeutic compound can beused to provide controlled in vivo adsorption of the therapeuticcompound over a discrete period of time.

In certain embodiments of the invention, the compound containing themetabolism reducing group, e.g., an ester group, is more active as atherapeutic agent for treating disorders than the corresponding compoundwithout the this group, e.g., due to a reduction in the production ofthe wake-promoting metabolite. In another embodiment of the invention,the compound containing the ester group, is more active as a therapeuticagent for treating disorders than the corresponding acid. In otherembodiments, the corresponding acid of the ester is not atherapeutically active agent for treating disorders.

One skilled in the art would recognize that the ester groups, asdescribed above, could be extended to thioesters. Labile amides may alsobe used in replacement of the ester group, wherein the in vivohydrolysis would be performed by peptidases in the CNS.

The language “biological activity” includes activity associated with theintended biological function of the compounds of the present invention,e.g., treating a sleep disorder.

The language “modulate a target” or “modulation of a target” includesthe act of agonizing or antagonizing a receptor or group of receptors ofa target disorder. Thus, a compound that agonizes or antagonizes areceptor or group of receptors is referred to herein as a targetmodulator, e.g., sleep disorder target modulator.

The language “target modulator” includes compounds or compositions,e.g., pharmaceutical compositions, which are used to modulate a target,e.g., a sleep disorder target.

The term “target” includes a receptor or group of receptors that havebeen identified as useful point of action for a therapeutic compound,e.g., sleep disorder target.

The language “receptor” includes specific sites of binding or actionwithin a is subject, associated or responsible for the activity of thetarget disorder, e.g., a 5-HT_(2A) receptor.

The language “group of receptors” includes two or more receptors thatmay comprise the same receptor type or may comprise two or more receptortypes.

The language “compounds that agonize” a receptor is intended to includecompounds that induce the activity of the receptor and agents thatup-regulate (i.e., induce) the synthesis or production of the receptor.

The language “compounds that antagonize” a receptor, e.g., a 5-HT_(2A)receptor, is intended to include compounds that inhibit the activity ofthe receptor and agents that down-regulate (i.e., inhibit) the synthesisor production of the receptor.

The terms “modification” or “modifies” include controlling or adjustingphysical or chemical parameters, e.g., the half-life, of the therapeuticcompound in vivo by changing one or more factors, e.g., thelipophilicity, electronic properties and/or steric size of themetabolite reducing moiety, e.g., ester group.

The language “spacer molecule,” “SP,” “SP,” or “SP₂” includes moleculesor moieties that are positioned within the compound to allow thecompound to perform its intended function. In certain embodiments, thespacer molecule may be present. Alternatively, in certain otherembodiments, the spacer molecule may not be present. In certainembodiments, the spacer molecule may be (CH₂)_(m), where m is an integernumber selected from 1 to 20. In addition, the spacer molecule, e.g.,the (CH₂)_(m) linker to an ester or a carboxylic acid group, can besubstituted with one or more substituents. In one embodiment, the spacermolecule is mono-substituted. In another embodiment of the invention,the spacer molecule is disubstituted. In particular embodiments, thelinkers of the invention may be geminally-dialkylated, e.g.,gem-dimethylated; singly substituted with a substituent other than anoncyclic alkyl group, e.g., a heteroatom; or a cyclic substituentwherein one or more of the carbons of the spacer molecule is containedin the ring, e.g., heterocycle (e.g., tetrahydropyran ortetrahydrofuran), or cyclic alkyl, e.g., cyclopropyl. However, thesubstitution of the spacer molecule is independent of the substitutionelsewhere in the molecule.

In particular, the therapeutic compound of the invention may comprisethe formula:[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

In certain embodiments of the invention, the therapeutic compound has afavorable biological property. In one embodiment of the invention, theinvention is a method of treating a sleep disorder. The method comprisesadministering an effective amount of a trazodone compound, such that thesleep disorder is treated, wherein the trazodone compound has afavorable biological property (FBP).

The language “favorable biological property (FBP)” includes one or morebiological properties that allow the compound to perform its intendedfunction in an enhanced manner. Examples of favorable biologicalproperties include but are not limited to induction of a discrete sleepor hypnotic state, activity of the therapeutic compound for a discreteperiod of time, penetration through the blood brain barrier into theCNS, modulation of the half-life of the therapeutic compound, in vivohydrolysis of the ester by esterases that allows sequestration of thetherapeutic compound in the CNS, reduction of the formation of awake-promoting metabolite, e.g., m-CPP, an alteration of charge, analteration of pharmacology-kinetics, an alteration of log P by a valueof 0.25 or more, increased receptor selectivity, reduced peripheralhalf-life, the ability to increase dosage, increased peripheralelimination, increased elimination from the CNS, decreasedanti-muscarinic activity, decreased anti-cholinergic, and anycombination thereof. It should be understood that the language “FPB” isintended to include a single property or a combination of two or moreproperties. In particular embodiments of the invention, the therapeuticcompound induces a discrete sleep or hypnotic state by penetration intothe CNS. In certain embodiments of the invention, the FBP includesincreased concentration within the CNS for a discrete period of time asa result of a slower rate of conversion to the corresponding carboxylicacid by in vivo esterase activity within the CNS as compared with theperiphery.

In certain embodiments, wherein the therapeutic compound is active for adiscrete period of time, the FBP is a reduced ability of the subject toform a tolerance to the therapeutic compound. The language “tolerance”includes the natural tendency of a subject to become less affected bycontinued administration of a particular therapeutic compound due torepeated exposure to the compound. It should be noted that tolerance istypically increased coincident with the increased time that a compoundis present in its active state within the subject. Reduced tolerancewould coincide with increased therapeutic effectiveness.

The language “discrete sleep or hypnotic state” includes a state ofsedated consciousness that is induced by the presence of activetherapeutic compound of the invention, for a defined period of time.This is in contrast to the lingering hangover effect resulting from theexisting treatments, e.g., anti-histamines, used for their sedativeeffect that maintain active drug concentrations for extended periods oftime in the periphery.

The language “discrete period of time” includes a defined period of timein which the therapeutic compound is active, and depends upon thephysical and reactive properties of the ester group. In one embodimentof the invention, the half-life of the therapeutic compound is 1 to 8hours. In a preferred embodiment, the half-life of the therapeuticcompound is 4 to 6 hours. It should be understood that ranges withinthese half-life values is intended to be within the scope of thisinvention.

The term “sequestration” includes having enhanced concentration in theCNS and more rapid elimination from the periphery. The product ofhydrolysis can exit the brain by various carboxylate excretionmechanisms, possibly at a slower rate than from the periphery producinga CNS sequestration of the carboxylate for a defined, or discrete,period of time. In one embodiment of the invention, elimination of thehydrolyzed carboxylate-containing metabolite occurs predominately byexcretion through the kidneys, due to enhanced polarity of themetabolite, either as the free carboxylate or after Phase II furthermetabolism. In another embodiment, elimination occurs predominantly bymetabolism in the liver, e.g. hydrolysis of the ester followed byglucuronidation, and excretion into the bile. In certain embodiments,the brain assists in the elimination from the CNS though various activetransport mechanisms.

Another embodiment of the current invention is a method of modulating asleep disorder target comprising administering to a subject an effectiveamount of a therapeutic compound, such that the sleep disorder istreated, wherein the therapeutic compound is as described above andcomprises one of the following formulae:[EG]_(r)-(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR], or[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the half-life of the therapeutic compound, SP, SP₁and SP₂ are spacer molecules, n, q, and r are independently 0 or 1, andr and q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound (i.e., EG=MR such that EG also reduces theformation of the wake-promoting metabolite).

Another embodiment of the invention is a sleep disorder target modulatorcomprising the formula:[EG]_(r)-(SP₂)_(q)-[TZ]-(SP₁)_(n)-[MR]wherein TZ is a trazodone compound, MR is a metabolite reducing moietythat reduces the formation of wake promoting metabolites, EG is an estergroup that modifies the half-life of the therapeutic compound, SP₁ andSP₂ are spacer molecules, n, q, and r are independently 0 or 1, and rand q are 0 when MR is the ester group that modifies the half-life ofthe therapeutic compound.

In another embodiment of the invention, a sleep disorder targetmodulator comprises the formula:[TZ]-(SP)_(n)-[EG]wherein TZ is a trazodone compound, EG is an ester group that modifiesthe half-life of the therapeutic compound, SP is a spacer molecule, andn is 0 or 1.

In accord with the invention, particular embodiments of the therapeuticcompound used for treating disorders are:

wherein a=0 through 5, b=0 through 5, b=0 through 5, and R is any groupwhich imparts properties to the therapeutic compound to promotepenetration into the CNS, reduction of the formation of wake-promotingmetabolites, and/or to modify the half-life of the compound. Inpreferred embodiments of the invention, a=0 or 1; b=0 or 1; and c=0 or1.

Additional particular embodiments of the therapeutic compound used fortreating disorders are:

wherein MR is a metabolite reducing moiety that reduces the formation ofwake-promoting metabolites. MR is selected and positioned along thedotted line shown above such that the compound is capable of performingits intended function.

In yet another particular embodiment, the therapeutic compound used fortreating disorders can have the formula:

wherein MR is a metabolite reducing moiety that reduces the formation ofwake-promoting metabolites, EG is an ester group that modifies thehalf-life of the therapeutic compound, SP is a spacer molecule, q is 0or 1, and X is H or Cl, such that MR is selected and positioned alongthe dotted line shown above such that the compound is capable ofperforming its intended function. It should be understood that MR can beone or more groups, i.e., functional moieties, which can be attached atmultiple positions along the dotted line (e.g., a single MR group may beattached at multiple positions or more than one MR group may be attachedat multiple positions). In certain embodiments, MR is alkyl. Inparticular embodiments, the therapeutic compound of the invention isselected from the compounds listed in Table 2. TABLE 2 Structure Series#

18d-oxa- late

18f-oxa- late

19d-oxa- late

18a-HCl

N/A

19a-HCl

19f-oxa- late

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

Free base

Free base

N/A

N/A

Free base

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

Another embodiment of the invention is a pharmaceutical compositioncomprising a therapeutic compound as prepared according to themethodology of this invention, and a pharmaceutically acceptablecarrier.

In another embodiment, the invention is intended to include any novelcompounds described herein.

Additionally, the compounds described above are intended to includeanalogs containing art-recognized substituents that do not significantlyeffect the analog's ability to perform its intended function.Furthermore, any novel synthesis of the compounds of the inventiondescribed herein, is also intended to be included within the scope ofthe present invention.

Assays can be used to design and/or select compounds useful within thepresent invention. The SCORE method, described in Example 2, would be anexample of such an assay. Multiple assay components, such as total sleeptime, cumulative nonREM sleep profile, maximum nonREM sleep bout length,average nonREM sleep bout length, nonREM sleep time, nonREM onset ofaction profile, sleep latency, REM sleep time, REM sleep bout length,cumulative REM sleep profile, maximum wake bout length, average wakebout length, locomotor activity, locomotor activity intensity, bodytemperature, and drinking are used to define compounds that would beuseful in the present invention. For example, in determining therapeuticcompounds that would be useful as sedatives or wake-promoting compounds,all of the components listed above would be used in determining apreferred therapeutic compound. Antidepressant therapeutic compoundswould use the components of total sleep time, cumulative nonREM sleepprofile, maximum nonREM sleep bout length, REM sleep time, REM sleepbout length, locomotor activity, locomotor activity intensity, and bodytemperature for determination of preferred therapeutic compounds.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples thatshould not be construed as limiting. Compounds described herein may beobtained through art recognized synthesis strategies.

EXAMPLE 1

Several synthetic protocols for compounds of the invention andintermediates thereto are described below and depicted in thecorresponding schemes, shown below.

Compound 1. Compound 1 was synthesized following the similar procedurereported by Lis, R.; Marisca, A. J. A Convenient Synthesis ofN-Aryl-N′-Benzyl-1,2-Ethanediamines. Synth. Commun. 1988, 18, 45-50.

Compound 2 and 3. Compound 1 (19.5 g, 60.93 mmol) and ethyl2,3-dibromopropionate (30.2 g, 117.36 mmol) were dissolved in DMF (55mL). Triethylamine (32.5 mL, 234.72 mmol) was added to give a slurry,which then was heated in an oil bath at 110° C. for 17 h. The reactionwas cooled to room temperature and 1 N NaOH (80 mL) was added. Theresulting solid was collected by filtration and crystallized from2-propanol to give 9.2 g of compound 3. The mother liquor was thenconcentrated and purified by column chromatography (silica) to givecompound 2 (4.1 g). Compound 2 and 3 were confirmed by ¹H-NMR, ¹³C-NMRand LC-MS.

Compound 5. Compound 2 (2.1 g, 5 mmol) and methoxybenzene (1.1 g, 10mmol) were added to a 5% solution of H₂SO₄ in CF₃COOH (12 mL). After thereaction was heated at 60° C. for 40 h, water (5 mL), 1 N NaOH (10 mL,saturated NaHCO₃ (10 mL), and CH₂Cl₂ (150 mL) were added. The organiclayer was separated and dried (Na₂SO₄) and the solvent was removed togive compound 5 (760 mg, 60%). Compound 5 was confirmed by ¹H-NMR andLC-MS.

Compound 4. Compound 4 was prepared from compound 2 in 75% yieldfollowing the same procedure as that for compound 5.

2-(3-chloropropyl)-1,2,4-triazo[4,3-a]pyridin-3(2H)-one(7). A mixture of1,2,4-triazo[4,3-a]pyridin-3(2H)-one (6), 1.35 g, 10 mmol),1-bromo-3-chloropropane (4.13 g, 26 mmol) and potassium carbonate (2.07g, 15 mmol) in MeCN ( 15 mL) was refluxed for 8 h. After removal of theinsoluble material by filtration, the filtrate was concentrated and theresidue was extracted with CHCl₃ (150 mL). After evaporation of thesolvent, the residual material was purified by column chromatography(EtOAc/Heptane, 1:2) to give2-(3-chloropropyl)-1,2,4-triazo[4,3-a]pyridin-3(2H)-one, compound 7(1.47 g, 70%). Compound 7 was confirmed by ¹H-NMR and LC-MS.

Compound 15. Compound 6, 1.45 g, 6.9 mmol) and1-(3-chlorophenyl)-2-carbethoxypiperazine (5) (1.75 g, 6.9 mmol) andtriethylamine (2 mL, 14.4 mmol) were taken up in xylene (20 mL) andrefluxed for 12 h. After cooling to room temperature, the solution waswashed with water and evaporated under reduced pressure. The residue wasdissolved in EtOAc (100 mL), washed with brine and dried (Na₂SO₄), andwas purified by column chromatography (EtOAc/Heptane, 2:3) to give thecompound 15 (1.65 g, 65%). Compound 15 was confirmed by ¹H-NMR andLC-MS.

Compound 19d. Sodium hydride (60% dispersion in mineral oil, about 60mg) was added to a stirred solution of 15 (2.2 g, 4.95 mmol) in2-propanol (15 mL). After 12 h, the solvent was removed under vacuum.The residue was then dissolved in EtOAc (100 mL), washed with brine,dried (Na2SO4), and purified by column chromatography (EtOAc/Heptane,1:2) to give the compound 19d (1.58 g, 70%/o). Compound 19d wasconfirmed by ¹H-NMR and LC-MS.

Compound 19d-Oxalate. A solution of oxalic acid (150 mg, 1.68 mmol) inethanol (1 mL) was added to a stirred solution of compound 19d (770 mg,1.68 mmol) in ethanol (1.25 mL) in one aliquot. The mixture became solidat the end of the addition and ethyl acetate (2 mL) was added tofacilitate stirring. After 1 h of stirring, the solid was collected bysuction and washed with ethyl acetate (5 mL). After drying, the oxalatesalt 19d-Ox was obtained as white powder (730 mg, 85%). ¹H-NMR andelemental analyses were consistent with the structure.

Compound 18a-HCl. Compound 14 (1.2 g, 2.7 mmol) was dissolved in MeOH(20 mL) and an aqueous solution of NaOH (2N) was added. The reaction wasrefluxed for 2 h and was cooled to room temperature. The solvents wereremoved and the residue was purified by using preparative HPLC to givethe sodium salt of 18a. The sodium salt was dissolved in MeOH (10 mL)and aqueous HCl ( 3 mL, 1 N) was added and stirred for 45 minutes. Thesolution was concentrated to give the compound 18a-HCl and was confirmedby ¹H-NMR, LC-MS and elemental analysis.

Trazodone with gem-dimethyl bridge

Compound 3. A mixture of 1,2,4-triazolo(4,3-a)pyridin-3(2H)-one (11.2 g,82.88 mmol) (1), 1,3-dichloro-2,2-dimethyl propane (2), and K₂CO₃ (23.0g, 21.71 mmol.) in DMF (100 mL) was stirred at 150° C. for 48 hours.Product 3 (5.4 g, 27% yield) was isolated by silica gel columnpurification and confirmed by ¹H-NMR, LC-MS.

Compound 5. Compound 3 (1.0 equivalent) was dissolved in DMF (25 mL).The amine (4) (1.5 equivalent) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU, 1.5 equivalent) were added to the solution, and the solution washeated to 150° C. for 48 h. Product 5, (12% to 20% yield) was isolatedafter silica gel column chromatography and confirmed by ¹H-NMR, LC-MS.

References: 1) G. B. Phillips et al, J. Med. Chem., 1992, 35, 743-750.2) G. Le Bihan et al, J. Med. Chem., 1999, 42, 1587-1603. 3) M.Giannangeli et al, J. Med Chem., 1999, 42,336-345.

References: 1) Stoller, A. et al, Tetrahedron Lett. (1990), 31(3),361-4. 2) Motherwell, W. B. et al, Contemp. Org. Synth. (1994), 1(4),219-241. 3) Simmons, H. E. et al, Org. React. (1973), 20, 1. 4)Woodworth, C. W. et al, Chem. Comm. (1968), 569-570.

EXAMPLE 2 Comparison of Trazodone and Trazodone Metabolite UsingSCORE-200™

Sleep-wakefulness, locomotor activity and body temperature weremonitored in Male Wistar rats treated with Trazodone (10 mg/kg, n=7) andthe principal metabolite of Trazodone, m-CPP (3 mg/kg, n=6 and lo mg/kg,n=7). Trazodone was administered at CT-18 (6 hours after lights-off).The Trazodone metabolite m-CPP was administered at CT-5 (5 hours afterlights-on). Trazodone disrupted sleep during the first hour but washighly soporific in subsequent hours. Trazodone sleep effects werecharacterized by increased nonREM sleep time and increased sleepcontinuity, but without evidence of REM sleep inhibition, reboundinsomnia, or disproportional locomotor activity changes. By contrast,the Trazodone metabolite m-CPP significantly interfered with nonREMsleep for 2-3 hours and REM sleep for 7 hours post-treatment. Theseeffects were followed by a rebound hypersomnolence. The temporal courseof m-CPP effects on sleep-wakefulness provide working evidence that theinitial efficacy and duration of Trazodone action on sleep-wake may begreatly enhanced by inactivating the m-CPP component of Trazodonemetabolism through medicinal chemistry modification of the Trazodonemolecule.

The general experimental conditions utilized in testing the compounds ofthe invention for their utility treating sleep disorders are describedbelow.

I. Animals & Surgery.

Adult, male Wistar rats (250 g at time of surgery, Charles RiverLaboratories) were anesthetized (Nembutal, 62 mg/kg) and surgicallyprepared with a cranial implant to permit chronic electro-encephalogram(EEG) and electromyogram (EMG) recording. Body temperature and locomotoractivity were monitored via a miniature transmitter (Minimitter)surgically placed in the abdomen. The cranial implant consisted ofstainless steel screws (two frontal [±3.2 AP from bregma, ±2.0 ML] andtwo occipital [−6.9 AP, ±5.5 ML]) for EEG recording. Two Teflon-coatedstainless steel wires were positioned under the nuchal trapezoid musclesfor EMG recording. All leads were soldered to a miniature connectorprior to surgery, and gas sterilized in ethylene oxide. The implantassembly was affixed to the skull with dental acrylic. A minimum ofthree weeks was allowed for surgical recovery.

II. Recording Environment.

Each rat was permanently housed in its own individual recording cagelocated within separate, ventilated compartments of custom-designedstainless steel cabinets. Each Nalgene microisolator cage was enhancedwith a filter-top riser and low-torque swivel-commutator. Food and waterwere available ad libitum. A 24-hr light-dark cycle (12 hours light, 12hours dark) was maintained throughout the study using 4-watt fluorescentbulbs 5 cm from the cage. Animals were undisturbed for at least 36 hoursbefore and after treatments.

III. Automated Physiological Monitoring.

Sleep and wakefulness were determined using “SCORE-2000™”—aninternet-based sleep-wake and physiological monitoring system. Thesystem monitors amplified EEG (bandpass 1-30 Hz; digitization rate 400Hz), integrated EMG (bandpass 10-100 Hz), body temperature andnon-specific locomotor activity (LMA) via telemetry, and drinkingactivity, continuously and simultaneously. Arousal states wereclassified on-line as NREM sleep, REM sleep, wake, or theta-dominatedwake every 10 seconds using EEG feature extraction and pattern-matchingalgorithms. The classification algorithm uses individually-taughtEEG-arousal-state templates, plus EMG criteria to differentiate REMsleep from theta-dominated wakefulness, plus behavior-dependentcontextual rules (e.g., if the animal was drinking, it was awake).Drinking and locomotor activity (LMA) were recorded as discrete eventsevery 10 seconds, while body temperature was recorded each minute.Locomotor activity was detected by a telemetry receiver (Minimitter,Sunriver, Oregon) beneath the cage. Telemetry measures (LMA and bodytemperature) were not part of the scoring algorithm; thus, sleep-scoringand telemetry data were independent measures.

IV. Treatments and Study Design.

A. Timing of treatment Compounds were administered at CT-18, the peak ofthe activity-dominated period, in order to ensure (i) prior wakefulnesswas sufficient to interact positively with hypnotic-drug effects, and(ii) sufficient time was allowed to view the time course of thetreatment effect before lights-on (6 hours post-treatment). TheTrazodone metabolite m-CPP was administered at CT-5, the middle of therodent rest-phase of the daily sleep-wake rhythm, in order to ensure (i)maximum assay sensitivity to the wake-promoting effects of the compound,and (ii) maximum assay sensitivity to compound effects on REM sleep.

B. Vehicle and route of administration. Compounds were suspended insterile 0.25% methylcellulose (1 ml/kg). Treatments were administered asan intraperitoneal bolus.

C. Study design and controls. A parallel group study design wasemployed. Vehicle controls were drawn from a large pool (N>200): asubset of the pooled vehicle controls was selected, based oncomputerized matching with the 24-hour pre-treatment baseline of theactive treatment group.

D. Drugs tested. Trazodone and the Trazodone metabolite m-CPP weretested for this proof of principle study. Trazodone was administered at10 mg/kg. The Trazodone metabolite m-CPP was administered at 3 mg/kg and10 mg/kg.

V. Results

Trazodone (10 mg/kg IP, n=7) interfered with sleep during the initial 2hours post-treatment but markedly and significantly increased nonREMsleep time (FIG. 1) and sleep bout duration for 2-3 hours thereafter(FIG. 2), and increased sleep consolidation in the initial 2-3 hours ofthe subsequent subjective day (lights-on phase of the LD 12:12light-dark cycle). Trazodone produced no evidence of rebound insomnia,disproportional motor inhibition, or adverse thermoregulatory eventspost-treatment. The sleep consolidating effects of Trazodone wereespecially noteworthy, as they were more robust in magnitude whencompared to comparable treatment with contemporary benzodiazepinesedative hypnotics such as zolpidem.

The Trazodone metabolite m-CPP (3 mg/kg IP, n=6, and 10 mg/kg IP, n=7)strongly and dose-dependently interfered with sleep 2-3 hourspost-treatment. Interference with sleep was characterized by adose-dependent reduction in nonREM sleep time lasting 2-3 hourspost-treatment, and a marked dose-dependent reduction in REM sleeplasting up to7 hours post-treatment at the higher dose. Sleepinterference caused by m-CPP was followed by rebound hypersomnolencereflected in both nonREM sleep and sleep bout-length measures. Thetimecourse of sleep interference (increased waking) caused by m-CPPcorrelated very strongly with the initial interference of sleepfollowing Trazodone treatment (noted above). In addition, the reboundhypersomnolence caused by m-CPP correlated very strongly with thetimecourse of carryover effects following Trazodone administration(noted above). Taken together, it is likely that the delayed onset ofTrazodone-induced sleep is caused in part or completely by thesleep-interference characteristics of the Trazodone metabolite m-CPP. Itis further likely that the soporific carryover effects of Trazodone arecaused in part or completely by the rebound hypersomnolence induced bythe Trazodone metabolite m-CPP.

V. Conclusions

Trazodone has considerable potential as a sedative hypnotic if theundesirable effects of the Trazodone metabolite m-CPP (sleepinterference, rebound hypersomnolence, REM sleep inhibition andsympathomimetic effects) could be inactivated through medicinalchemistry modification of the Trazodone molecule. On the basis of thedata from this study, it is anticipated that the efficacy of Trazodonewill be increased, and drug carry-over will be decreased, throughinactivation of the Trazodone metabolite m-CPP.

EXAMPLE 3 Comparison of Trazodone and Trazodone Analog Using SCORE-2000™

Sleep-wakefulness, locomotor activity and body temperature weremonitored in Male Wistar rats treated with Trazodone (30 mg/kg, n=9) andHY-2725 (I9) (30 mg/kg, n=8). The general experimental conditionsutilized in testing the compounds of the invention for their utilitytreating sleep disorders are described in Example 2.

Results

Trazodone initially interferes with sleep (FIG. 5: arrow; lower plot)whereas HY-2725 has a more rapid soporific onset of action and does notinterfere with sleep (FIG. 2: upper plot). The initial interference insleep after trazodone treatment is believed to be caused by theformation of the Trazodone metabolite m-CPP. HY-2725 is designed toreduce or eliminate the formation of this metabolite.

FIG. 6 demonstrates that Trazodone treatment (triangle) inhibits REMsleep (FIG. 6: arrows, lower plot), whereas HY-2725 does not inhibit REMsleep.

In addition, HY-2725, a cyclopentyl ester analog, potently anddose-dependently increases sleep consolidation after treatment (FIG. 7:triangle).

Several interesting SCORE components determined for the parent Trazodonecompound and Compound 19f are shown below. Compound 19f shows notinitial sleep interference and no REM sleep inhibition, whereasTrazodone shows significant initial sleep interference and significantREM sleep inhibition. In addition the duration of action of 19f issignificantly decreased as compared with Trazodone.

Summary of Findings using the SCORE-2000™ Sleep-Wake Assay: CompoundTRAZODONE 19f Initial Sleep Interference ++++ None REM Sleep Inhibition++++ None Increase Sleep Consolidation +++ ++++ Increase Sleep Time ++++++ Rebound Insomnia None None Disproportional Motor Inhibition NoneNone Body Temp (CV) Adverse Event Yes No Duration of Action 7-9 h 5-6 hConclusions

As discussed in Example 2, Trazodone has considerable potential as asedative hypnotic if the undesirable effects of the Trazodone metabolitem-CPP (sleep interference, rebound hypersomnolence, REM sleep inhibitionand sympathomimetic effects) could be inactivated through medicinalchemistry modification of the Trazodone molecule. On the basis of thedata from this study, including the experimental results obtained forCompound 19f, it is anticipated that the efficacy of Trazodone will beincreased, and drug carry-over will be decreased, through inactivationof the Trazodone metabolite m-CPP.

EXAMPLE 4 Determination of Activity of Carboxylic Acid DerivatizedTrazodone Compound

Sleep-wakefulness, locomotor activity and body temperature weremonitored in Male Wistar rats treated with HY-2724 (a) (30 mg/kg, n=7).The general experimental conditions utilized in testing the compounds ofthe invention for their utility treating sleep disorders are describedin Example 2.

Results

FIG. 8 shows that the acid (L9a) form of HY-2725 (9f; cyclopentyl ester)is ineffective in increasing sleep and sleep consolidation. HY-2724 wasinactive on sleep-wakefulness in all measured variables.

Conclusions

On the basis of the data from this study, it would appear that thecorresponding acid becomes inactive once metabolized from the ester tothe acid form, e.g., by esterases. This “deactivation” of the activecompound should provide an ability to sufficiently control (modify) thehalf-life of the ester derivatized compounds.

EXAMPLE 5 5-HT_(2A) Binding Study

Binding assays were performed on Trazodone, HY-2725 (19f), HY-2650 (19d)and HY-2724 (19a), described above, using both rat and human 5-HY_(2A)receptor. The results are shown in Table 3.

The binding studies against the 5-HT_(2A) receptor, indicate bindingaffinity, and therefore the results of the binding assays are anindication of the activity of the compound.

Table 3 shows rat and human 5-HT_(2A) receptor binding for theabove-identified compounds. Soporific efficacy and sleep consolidationparalleled binding affinity at 5-HT_(2A) for HY-2725, HY-2650 andHY-2724. Although HY-2725 binding affinity is shown as less than that ofTrazodone, however, the HY2725 compound used was a racemic mixture oftwo isomers. Thus, the effective binding affinity of HY-2725 may beequal or nearly equal to that of Trazodone. It is hypothesized thatHY-2725 soporific efficacy is superior to Trazodone because HY-2725 doesnot produce the metabolite m-CPP. TABLE 3 5HT-2a (Ki nM) CompoundSide-Chain Rat Human Trazodone none 8.11 286 HY-2725 cyclopentyl 18.7757 HY-2650 isapropyl 50.3 2,103 HY-2724 acid 989 >10,000

INCORPORATED BY REFERENCE

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1.-128. (canceled)
 129. A method of treating a sleep disorder,comprising administering to a subject an effective amount of a trazodonecompound, such that the sleep disorder is treated, wherein saidtrazodone compound is represented by the formula:

wherein MR is a metabolite reducing moiety that reduces the formation ofwake-promoting metabolites, MR is attached to a carbon along the dottedline shown, EG is an ester group that modifies the half-life of thetrazodone compound, SP is a spacer molecule, q is 0 or 1, X is H or Cl.130. The method of claim 129, wherein said spacer molecule is (CH₂)_(m),where m is an integer selected from 1 to
 20. 131. The method of claim129, wherein said trazodone compound containing MR is more effective asa therapeutic agent for treating a sleep disorder than the correspondingcompound without the MR.
 132. The method of claim 129, wherein saidtrazodone compound containing said EG is more effective as a therapeuticagent for treating a sleep disorder than the corresponding compoundwithout the EG.
 133. The method of claim 129, wherein said trazodonecompound containing EG is more effective as a therapeutic agent fortreating a sleep disorder than the corresponding acid of said EG. 134.The method of claim 129, wherein said trazodone compound containing thecorresponding acid of EG is not a therapeutically effective agent fortreating a sleep disorder.
 135. The method of claim 129, wherein saidwake promoting metabolite is m-CPP.
 136. The method of claim 129,wherein the trazodone compound induces a discrete sleep or hypnoticstate by penetration into the Central Nervous System (CNS).
 137. Themethod of claim 129, wherein the sleep disorder is selected from thegroup consisting of insomnia, hypersomnia, narcolepsy, sleep apneasyndromes, parasomnia, restless leg syndrome, and circadian rhythmabnormality.
 138. The method of claim 137, wherein the sleep disorder isinsomnia.
 139. The method of claim 137, wherein the sleep disorder ishypersomnia.
 140. The method of claim 137, wherein the sleep disorder isnarcolepsy.
 141. The method of claim 137, wherein the sleep disorder issleep apnea syndrome.
 142. The method of claim 137, wherein the sleepdisorder is parasomnia.
 143. The method of claim 137, wherein the sleepdisorder is restless leg syndrome.
 144. The method of claim 137, whereinthe sleep disorder is circadian rhythm abnormality.
 145. The method ofclaim 144, wherein the circadian rhythm abnormality is selected from thegroup consisting of jet lag, shift-work disorders, and delayed oradvanced sleep phase syndrome.
 146. The method of claim 129, wherein thetrazodone compound is administered orally.
 147. The method of claim 129,further comprising administering the trazodone compound in apharmaceutically acceptable vehicle.
 148. The method of claim 129,wherein MR is one or more moieties that are attached at one or morepositions along the dotted line.
 149. The method of claim 148, whereinMR is a single moiety that is attached at multiple positions.
 150. Themethod of claim 148, wherein MR is more than one moiety attached atmultiple positions.
 151. The method of claim 129, wherein MR is an alkylgroup.
 152. The method of claim 129, wherein MR is selected from the MRsrepresented in the compounds listed in Table
 2. 153. The method of claim152, wherein MR is selected from a methyl, a geminal dimethyl, acyclopropyl, a COOH, a COO-ethyl, a COO-isopropyl, a COO-cyclopentyl, aCOO-pentyl, a cycloheptyl, and a benzyl group.
 154. The method of claim149, wherein MR is cyclopropyl.
 155. A method of treating a sleepdisorder, comprising administering to a subject an effective amount of atrazodone compound, such that the sleep disorder is treated, whereinsaid trazodone compound is represented by the formula:

wherein MR is selected from a geminal dimethyl, a cyclopropyl, a COOH, aCOO-ethyl, a COO-isopropyl, a COO-cyclopentyl, a COO-pentyl, acycloheptyl, and a benzyl group.
 156. A method of treating a sleepdisorder, comprising administering to a subject an effective amount of atrazodone compound, such that the sleep disorder is treated, whereinsaid trazodone compound is selected from the group consisting of:

wherein a, b, and c are, independently, selected from 0, 1, 2, 3, 4, andS. and R is any group which imparts properties to the trazodone compoundto promote reduction of formation of wake-promoting metabolites, andmodification to the half-life of the compound.
 157. The method of claim156, wherein a is 0 or
 1. 158. The method of claim 156, wherein b is 0or
 1. 159. The method of claim 156, wherein c is 0 or
 1. 160. The methodof claim 156, wherein R is selected from the group consisting ofhydrocarbons and perfluorocarbons.
 161. The method of claim 160, whereinthe hydrocarbons are selected from the group consisting of linear;branched; cyclic; aromatic; and a combination of saturated orunsaturated aliphatic and aromatic; wherein further the hydrocarbons areoptionally substituted with O, N, S, or halogen and may additionallyinclude one or more centers of chirality.
 162. The method of claim 160,wherein the hydrocarbons contain from 1 to 20 carbons.
 163. The methodof claim 156, wherein R is selected from the group consisting of amethyl, an ethyl, an n-propyl, an isopropyl, a t-butyl, an isobutyl, acyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.
 164. Themethod of claim 163, wherein R is a cyclohexyl group.
 165. The method ofclaim 163, wherein R is a cyclopentyl group.
 166. The method of claim163, wherein R is a cycloheptyl group.
 167. The method of claim 163,wherein R is an isobutyl group.
 168. The method of claim 163, wherein Ris an ethyl group.
 169. The method of claim 163, wherein R is a methylgroup.
 170. The method of claim 163, wherein R is an n-propyl group.171. The method of claim 163, wherein R is an isopropyl group.
 172. Themethod of claim 163, wherein R is a t-butyl group.
 173. The method ofclaim 163, wherein R is a benzyl group.
 174. The method of claim 163,wherein R is a bulky alcohol.
 175. The method of claim 174, wherein thebulky alcohol is selected from the alcohols listed in Table
 1. 176. Amethod of treating a sleep disorder, comprising administering to asubject an effective amount of a trazodone compound, such that the sleepdisorder is treated, wherein said trazodone compound is represented bythe formula:

wherein R₁ and R₂ are, independently, selected from H, COO-isopropyl,and COO-cyclopentyl, provided that at least one of R₁ and R₂ is not H.177. The method of claim 176, wherein one of R₁ and R₂ is H.
 178. Acompound of the formula:

wherein MR is a metabolite reducing moiety that reduces the formation ofwake-promoting metabolites, MR is attached to a carbon along the dottedline shown, EG is an ester group that modifies the half-life of thetrazodone compound, SP is a spacer molecule, q is 0 or 1, X is H or Cl.179. The compound of claim 178, wherein said wake promoting metaboliteis m-CPP.
 180. The compound of claim 178, wherein said spacer moleculeis (CH₂)_(m), where m is an integer selected from 1 to
 20. 181. Thecompound of claim 178, wherein MR is one or more moieties attached atone or more positions along the dotted line.
 182. The compound of claim181 wherein MR is a single moiety that is attached at multiplepositions.
 183. The compound of claim 181, wherein MR is more than onemoiety attached at multiple positions.
 184. The compound of claim 178,wherein MR is an alkyl group.
 185. The compound of claim 178, wherein MRis selected from the MRs represented in the compounds listed in Table 2.186. The compound of claim 185, wherein MR is selected from methyl,geminal dimethyl, cyclopropyl, COOH, COO-ethyl, COO-isopropyl,COO-cyclopentyl, COO-pentyl a cycloheptyl, and benzyl.
 187. The compoundof claim 181, wherein MR is cyclopropyl.
 188. A compound represented bythe formula:

wherein MR is selected from a geminal dimethyl, a cyclopropyl, a COOH, aCOO-ethyl, a COO-isopropyl, a COO-cyclopentyl, a COO-pentyl, acycloheptyl, and a benzyl group.
 189. A compound selected from:

wherein a, b, and c, are, independently selected from 0, 1, 2, 3, 4, and5, and R is any group which imparts properties to the trazodone compoundto promote reduction of formation of wake-promoting metabolites, andmodification to the half-life of the compound.
 190. The compound ofclaim 189, wherein a is 0 or
 1. 191. The compound of claim 189, whereinb is 0 or
 1. 192. The compound of claim 189, wherein c is 0 or
 1. 193.The compound of claim 189, wherein R is selected from the groupconsisting of hydrocarbons and perfluorocarbons.
 194. The compound ofclaim 193, wherein the hydrocarbons are selected from the groupconsisting of linear; branched; cyclic; aromatic; and a combination ofsaturated or unsaturated aliphatic and aromatic; wherein further thehydrocarbons are optionally substituted with O, N, S, or halogen and mayadditionally include one or more centers of chirality.
 195. The compoundof claim 193, wherein the hydrocarbons contain from 1 to 20 carbons.196. The compound of claim 189, wherein R is selected from the groupconsisting of a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl,a t-butyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzylgroup.
 197. The compound of claim 196 wherein R is a cyclohexyl group.198. The compound of claim 196, wherein R is a cyclopentyl group. 199.The compound of claim 196, wherein R is a cycloheptyl group.
 200. Thecompound of claim 196, wherein R is an isobutyl group.
 201. The compoundof claim 196, wherein R is an ethyl group.
 202. The compound of claim196, wherein R is a methyl group.
 203. The compound of claim 196,wherein R is an n-propyl group.
 204. The compound of claim 196, whereinR is an isopropyl group.
 205. The compound of claim 196, wherein R is at-butyl group.
 206. The compound of claim 196, wherein R is a benzylgroup.
 207. The compound of claim 178, wherein said compound isformulated to provide controlled in vivo absorption of the compound overa discrete period of time.
 208. A compound having the formula:

wherein R₁ and R₂ are, independently, selected from H, COO-isopropyl,and COO-cyclopentyl, provided that at least one of R₁ and R₂ is not H.209. The compound of claim 208, wherein one of R₁ and R₂ is H.